Microbial infection in humans and animals is caused by pathogenic microorganisms including, for instance, bacteria, virus, fungi and protozoa. Treatment of bacteria and virus is today primarily effected by antibiotics and antivirals, respectively, which all are low-molecular weight compounds. Antibiotics (such as penicillin and rifampicin) are designed to attack the synthesis of the cell wall and to enter the bacterium and inhibit, for instance, the nucleotide synthesis, DNA replication and protein synthesis, or other important processes, without or only slightly affecting these or other activities in the human cell.
A serious problem is that many bacterial strains have evolved ways to adapt or to become resistant to the currently available antibiotics. The costs of developing new antibiotics is therefore very high and has to a great extent deterred commercial pharmaceutical companies from investing in this area.
Recently, there is a lot of commercial interest and effort in developing so-called cationic peptides. It has been found that virtually all organisms from microbes to man have a variety of cationic peptides that have a potent broad spectrum of antimicrobial activity, including activity against bacteria, eukaryotic parasites, viruses and fungi. The cationic peptides, which typically range in size from 12-50 amino acids and have molecular masses less than 10000, are amphiphatic, meaning that they possess both a hydrophobic group that interacts with, for instance, lipids and a positively charged group that interacts with negatively charged groups in the pathogenic bacterium. These peptides are small enough to penetrate the bacterial wall and affect chemical reactions vital for the metabolism of this bacterium. The action mode is, thus, similar to that of conventional antibiotics and, accordingly, one may expect the resistance problem to be the same.
In addition to the expected resistance problems, cationic peptides are toxic and, further, they cannot be mass-produced in bacteria or fungi in the way many other conventional antimicrobial drugs are produced. Many research groups all over the world in academia and industry have been heavily engaged in this area but no commercial products have been launched in spite of the huge investments.
The difficulties to find novel antibacterials without resistance problems have been compared with the difficulties to “find a needle in a haystack”, and there is therefore a need of a completely novel type of antiinfectional.
WO 2009/017456 A1 discloses the development of a different type of antibiotics which does not enter the bacterium (to affect its metabolism) but reacts with the bacterium membrane to immobilize the bacterium and in that way prevents the bacterium from multiplying, thereby making it harmless to the human cell.
That approach is based on the finding that bioparticles, such as cells (including bacteria), virus, fungi, spores, etc have several similarities in their surface properties, including a net surface charge that is negative, external hydrophobic groups, for instance lipids, and external hydrophilic groups, for instance carbohydrates. All types of bioparticles would therefore become attached to a support containing hydrophobic and/or positively charged groups and/or aromatic groups, such as phenol groups. Since it was also known that the more pathogenic a microorganism is, the higher is its surface hydrophobicity and the more it differs from the surface hydrophobicity of human cells, a pathogenic microorganism would attach stronger to a hydrophobic polymer or particle than would a human cell, if at all. As disclosed in WO 2009/017456 A1, pathogenic bioparticles may thus be made non-pathogenic by forming complexes with the above appropriate materials.
It is also found that at least some conventional antibiotics modify the surface structure of bacteria to become more negatively charged and less hydrophobic so that they will not or only weakly attach to human body cells, which was not reported in literature earlier. The common explanation is that conventional antibiotics disturb a chemical reaction of importance for the survival of the pathogen so much that it becomes inactive.
Accordingly, in the above-mentioned WO 2009/017456 A1 a pharmaceutical composition is disclosed which comprises a product for adsorption purposes, preferably in particulate form or polymeric form, especially for oral use or intravenous use, consisting of a support matrix which is insoluble or swelling in water and which supports a hydrophobic entity alone or in combination with a positively charged entity. The support matrix may be a polysaccharide, preferably cellulose. The hydrophobic entity may e.g. be a saturated or unsaturated hydrocarbon chain, and the positively charged entity may e.g. be an amino or ammonium group. A similar product for non-medical or non-therapeutical absorption purposes, especially for the absorption of airborne and/or liquid borne microbes as well as viruses, and microbial antigens including allergens, is disclosed in WO 2004/110193 A1.
As a substantial advantage of the pharmaceutical composition is mentioned the fact that the same method could be used for the attachment of all kinds of bioparticles, which makes the commercial production of the antibacterials, antivirals etc more cost-effective.
In support of the function of the new antibiotics disclosed in WO 2009/017456 A1, it is referred therein (in the “Examples” part) to Wadström, T., et al., Scand. J. Infect. Dis. 13:129-137, 1981, which describes experiments where rabbits were orally infected by enterotoxigenic E. coli bacteria to induce diarrhea. By feeding the rabbits with agarose beads derivatized with palmitoyl groups, the diarrhea ceased. No charged groups were attached to the beads.
In WO 2009/017456 A1 it is also referred to a successful treatment of a virus-infected horse by the administration of silica particles derivatized with hydrophobic groups. No charged groups were attached to the beads.
It would, however, be desirable to have access to antibiotics and other anti-microbials which, in addition to the advantages of the antibiotics described in WO 2009/017456 A1, also have a still higher specificity (selectivity). It is an object of the present invention to provide such antiinfectionals.